Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood and an important cause of short and long-term disability. Systemic Onset Juvenile Idiopathic Arthritis (SoJIA) represents up to 20percent of all the cases of JIA. This disease does not respond to conventional therapies or anti-TNF agents and it leads to serious disabilities in a large proportion of patients. During the past 4 years we have addressed most of the aims that were included in our original application. This has resulted in the following advances: 1) identification of Interleukin-1 as a major mediator of the systemic phase of the disease, 2) resolution of clinical symptoms upon initiation of IL-1 blockade, 3) identification of a signature specific to the initial, systemic phase of the disease that permits to establish the diagnosis against a panel of other febrile illnesses, 4) identification of the cell type that gives rise to this SoJIA-specific signature, 5) identification of environmental agents that trigger a dysregulated IL-1B production by SoJIA blood cells, 6) identification of the neutrophil as a potential major source of IL-1B in SoJIA, 7) identification of transcripts that are differentially regulated in SoJIA versus healthy controls in response to environmental agents. These transcripts represent candidates for genetic analysis. Our hypothesis is that SoJIA arises as the result of an inappropriate response of the innate immune system to an environmental insult. This inappropriate response very likely has a genetic basis. Having identified one of the potential triggers of IL-1 overproduction, and counting on an in vitro assay to test the effect of these and novel triggers on cells from patients and controls, we are now in a good position to select candidate genes for genetic and functional analyses. The specific aims of our current application are: 1. To confirm and extend our observations that candidate blood gene signatures are SoJIA-specific and can be used as diagnostic tools. 2. To further characterize the cell type(s) giving rise to the unique SoJIA gene signature. 3. To characterize the role of infectious agents in the initial stage and acute exacerbations/flare-ups of patients with SoJIA. Completion of these studies will set the stage for future experiments aimed at characterizing candidate genes at the genetic level and at ascertaining their contribution to IL-1B dysregulation. To perform these studies, we have secured collaborations with infectious disease experts, statisticians, geneticists and experts in the biology and regulation of IL-1 activation. The results of these studies will have immediate clinical and basic immunology applications and should contribute to improve the outlook of children suffering from this often devastating disease. PUBLIC HEALTH RELEVANCE: The successful accomplishment of this project would have significant consequences on SoJIA patients, including the availability of a simple diagnostic test and the identification of potential environmental triggers that may lead to novel therapeutic and/or preventive approaches. These studies will also set the stage for future discovery of susceptibility genes that could be used for screening and diagnostic purposes as well. Understanding the basis of IL-1 dysregulation might shed light on very basic aspects of cytokine biology and help finding novel therapeutic targets for this disease.